Ester substituted ion channel blockers and methods for use

Abstract

The invention provides compounds of Formula (I), or pharmaceutically acceptable salts thereof:The compounds, compositions, methods and kits of the invention are useful for the treatment of pain, itch, and neurogenic inflammation.

What is claimed is: 
     
       1. A compound represented by Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein:
 Y −  is a pharmaceutically acceptable anion; 
 R A  is CO 2 R T ; 
 R T  is substituted or unsubstituted alkyl; 
 R B  is H, D, halogen, or substituted or unsubstituted alkyl; 
 R C  is selected from as H, D, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, OR I , CN, NR J R K , NR L C(O)R M , S(O)R N , S(O) 2 R N , SO 2 NR Q R R , SO 3 R S , CO 2 R T ; C(O)R U , and C(O)NR V R W ; 
 each of R I , R J , R K , R L , R M , R N , R Q , R R , R S , R U , R V , and R W  is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; or R J  and R K  or R V  and R W  or R Q  and R R  can also be taken together with the nitrogen to which they are attached to form a substituted or unsubstituted 5, 6, 7, or 8 membered ring; 
 X I  is —NR Z C(O)—; 
 R Z  is H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, and substituted or unsubstituted heteroalkyl; 
 each of R D  and R E  is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, and substituted or unsubstituted cycloalkyl; 
 or R D  and R E  together with the carbon to which they are attached form a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted heterocyclic; 
 or R D  and R Z  together with the carbon and the —NC(O)— to which they are attached form a substituted or unsubstituted lactam; 
 wherein R F  and R G  together with the N +  to which they are attached form an substituted 5- to 9-membered heterocyclic ring having zero, one, or more heteroatoms in addition to the N + , wherein the substituent is selected from the group consisting of phenyl, CO 2 R 1T  and C(O)NR 1V R 1W  wherein R 1T , R 1V , and R 1W  is independently selected from H, D, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; 
 R H  is selected from substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted —C 6 -C 10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted —CH 2 -C 5 -C 10  aryl, and substituted or unsubstituted —CH 2 -C 5 -C 10  heteroaryl. 
 
     
     
       2. The compound of  claim 1 , wherein R T  is methyl or ethyl. 
     
     
       3. The compound of  claim 1 , wherein X 1  is —NHC(O)—. 
     
     
       4. The compound of  claim 1 , wherein R B  is methyl, and R C  is selected from the group consisting of hydrogen, methyl, halogen, nitrile, methoxy, and ethoxy. 
     
     
       5. The compound of  claim 1 , wherein R B  are methyl and R C  is hydrogen. 
     
     
       6. The compound of  claim 1 , wherein each of R D  and R E  is independently selected from hydrogen, D, substituted or unsubstituted alkyl; or R D  and R E  together form a substituted or unsubstituted C 3 -C 6  cycloalkyl or substituted or unsubstituted heterocyclic. 
     
     
       7. The compound of  claim 6 , wherein R D  and R E  are both hydrogen. 
     
     
       8. The compound of  claim 6 , wherein R D  is hydrogen and R E  is a C 1 -C 4  alkyl. 
     
     
       9. The compound of  claim 8 , wherein R D  is hydrogen and R E  is methyl, ethyl, n-propyl, or n-butyl. 
     
     
       10. The compound of  claim 6 , wherein R D  and R E  are taken together with the carbon to which they are attached to form a substituted or unsubstituted C 3 -C 6  cycloalkyl. 
     
     
       11. The compound of  claim 1 , wherein R H  is a substituted or unsubstituted —CH 2 -C 5 -C 10  aryl, or a substituted or unsubstituted —CH 2 -C 5 -C 10  heteroaryl. 
     
     
       12. The compound of  claim 11 , wherein R H  is a unsubstituted benzyl substituted by a C 1 -C 4  alkyl, halogen, methoxy, ethoxy, and cyano. 
     
     
       13. A compound selected from those in the Table below: 
       
         
           
                 
                 
               
                     
                 
                   Com- 
                     
                 
                   pound 
                   Structure 
                 
                     
                 
                   14A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   15A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   16A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   17A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   18A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   19A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   20A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   21A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   22A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   23A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   24A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   26A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   27A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   28A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   29A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   30A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   31A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   32A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   33A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   34A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   35A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   36A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   37A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   38A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   39A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   40A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   41A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   42A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   43A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   44A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   45A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   46A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   47A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   48A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   49A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   50A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   51A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   52A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   53A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   54A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   55A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   56A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   57A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   58A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   59A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   60A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   61A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   62A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   63A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   64A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   65A 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
       14. A pharmaceutical composition comprising the compound of  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 
     
     
       15. The composition of  claim 14 , wherein said composition is formulated for oral, intravenous, intramuscular, rectal, cutaneous, subcutaneous, topical, transdermal, sublingual, nasal, inhalation, vaginal, intrathecal, epidural, or ocular administration. 
     
     
       16. A method for treating pain, cough, itch, or a neurogenic inflammatory disorder in a patient, comprising administering to said patient an effective amount of a compound of  claim 1 . 
     
     
       17. The method of  claim 16 , wherein said pain is selected from the group consisting of pain due to back and neck pain, lower back pain, cancer pain, gynecological and labor pain, fibromyalgia, arthritis, rheumatoid arthritis, osteoarthritis, rheumatological pains, orthopedic pains, acute and post herpetic neuralgia and other neuropathic pains, sickle cell crises, vulvodynia, peri-anal pain, irritable bowel disease, irritable bowel syndrome, inflammatory bowel disease, oral mucositis, esophagitis, interstitial cystitis, urethritis and other urological pains, dental pain, headaches, trigeminal trophic syndrome, erythromelalgia, abdominal wall pain, chronic abdominal wall pain, allergic rhinitis, muscle pain, rectal pain, Levator ani syndrome, proctalgia fugax, hemorrhoid pain, stomach pain, skin ulcers, stomach ulcers, burn pain, ophthalmic irritation, conjunctivitis, eye redness, dry eye, dry eye syndrome, complex regional pain syndrome, post-surgical ocular pain, postoperative pain, acute postoperative pain, and procedural pain. 
     
     
       18. The method of  claim 16 , wherein said cough is selected from the group consisting of cough in patients with asthma, COPD, asthma-COPD overlap syndrome (ACOS), interstitial pulmonary fibrosis (IPF), idiopathic pulmonary fibrosis, post viral cough, post-infection cough, chronic idiopathic cough and lung cancer. 
     
     
       19. The method of  claim 16 , wherein said itch is selected from the group consisting of itch due to pruritus, brachioradial pruritus, chronic idiopathic pruritus, genital/anal pruritus, notalgia paresthetica, scalp pruritus, allergic dermatitis, contact dermatitis, atopic dermatitis, hand eczema, poison ivy, infections, parasites, insect bites, pregnancy, metabolic disorders, liver or renal failure, drug reactions, allergic reactions, eczema, genital and anal itch, hemorrhoid itch, and cancer. 
     
     
       20. The method of  claim 16 , wherein said neurogenic inflammatory disorder is selected from the group consisting of allergic inflammation, asthma, chronic cough, conjunctivitis, rhinitis, psoriasis, inflammatory bowel disease, interstitial cystitis, arthritis, colitis, contact dermatitis, diabetes, eczema, cystitis, gastritis, migraine headache, rosacea, sunburn, pancreatitis, chronic rhinosinusistis, traumatic brain injury, polymicrobial sepsis, tendinopathies, chronic urticaria, rheumatic disease, acute lung injury, exposure to irritants, inhalation of irritants, pollutants, chemical warfare agents, and atopic dermatitis.